Several lines of investigation have been pursued to elucidate the role of the sympathetic nervous system (SNS) and norepinephrine (NE) metabolism in hypertension. Total methoxyhydroxyphenyl glycol (MHPG) excretion in human urine correlates highly (p less than 0.001) with both creatinine excretion and body weight. Mean MHPG excretion is identical for normotensive and hypertensive populations, but nonetheless correlates highly (P less than 0.001) with systolic pressure within each population. Studies with the sympatholytic agents clonidine and guanethidine, and studies of patients with idiopathic orthostatic hypotension and pheochromocytoma support the idea that MHPG arises predominantly from peripheral NE metabolism and thus reflects sympathetic tone. One can use MHPG to quantitate the contribution of the SNS to essential hypertension and thus provide specific therapy for individual hypertensives. MHPG-sulfate excretion rates may allow quantitation of central nervous system (CNS) NE turnover. Work on NE release from rat cortex synaptosomes in a superfusion system allows a unique parallel to clinical observations on MHPG and provides a method for assessing the role presynaptic alpha-receptors in modulating CNS NE release.